The spleen is important for removing cellular debris. Central to this function are a specialized set of macrophages that recognize and capture particulate matter from circulation. In Systemic Lupus Erythematosus it is suggested that defective function of macrophages to clear dear cells promotes disease development and progression. However, how this occurs on a functional level is unknown. To examine this we removed macrophages from the spleen of mice that spontaneously develop lupus-like disease and found this greatly increased autoimmunity signifying splenic macrophages play an important role in preventing systemic autoimmunity. We subsequently found that dead cells induce expression of an enzyme that degrades the essential amino acid tryptophan and is important immune tolerance. Further we found blockade of this enzyme, indoleamine 2-3 dioxygenase, greatly altered the way macrophages respond to dead cells and lead to increased autoimmune disease activity in lupus-prone animals. The data strongly indicate that this activity may be important in the prevention immune responses to self-determinants in a novel regulatory mechanism. Our project will examine how dead cells induce indoleamine 2-3 dioxygenase (IDO) expression, how expression of the enzyme impacts apoptotic cell-mediated tolerance, and mechanisms by which IDO may influence lymphocyte and dendritic cell behavior. The findings of this project could have enormous implications in treatment of chronic inflammatory disease providing greater understanding of the basic biology as well as new therapeutic targets.